CN1510032A - Oxazolidone compound, preparing method and use thereof - Google Patents

Oxazolidone compound, preparing method and use thereof Download PDF

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Publication number
CN1510032A
CN1510032A CNA021577358A CN02157735A CN1510032A CN 1510032 A CN1510032 A CN 1510032A CN A021577358 A CNA021577358 A CN A021577358A CN 02157735 A CN02157735 A CN 02157735A CN 1510032 A CN1510032 A CN 1510032A
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phenyl
fluoro
oxo
piperazinyl
oxazolidinyl
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CN1237056C (en
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杨玉社
崔英杰
嵇汝运
陈凯先
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Shanghai Institute of Materia Medica of CAS
Nanjing Changao Pharmaceutical Science and Technology Co Ltd
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Shanghai Institute of Materia Medica of CAS
Nanjing Changao Pharmaceutical Science and Technology Co Ltd
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Abstract

The present invention provide as following formula (I) show oxazolidinone compounds and its salt: in formula R expression
Figure 02157735.8_AB_0
Or-NR2R3; wherein R1=can substituted alkyl sulphonyl; it can substituted aryl sulfonyl; it can substituted aromatic heterocycle sulfonyl; it can substituted amino acid formoxyl; can substituted aryl formoxyl, can substituted aryl-amino-carbonyl, can substituted arylamino thioformyl; R2=can substituted alkyl sulphonyl, can substituted aryl sulfonyl, can substituted aryl formoxyl, can substituted aromatic heterocycle formoxyl; R3=H or alkyl. The present invention also provides the preparation method of such compound and the applications on the preparation treatment infectious diseases especially drug of the microbial infection of multidrug resistance.

Description

Oxazolidinone compounds, Preparation Method And The Use
technical field
The present invention relates to pharmaceutical chemistry and chemotherapy field, Ju body She is Ji the purposes in the synthetic and treatment infectious diseases of oxazolidinone compounds, the infectious diseases that particularly causes at multidrug resistance.
background technology
Therefore and the superbacteria (superbugs) of the resistance to Multiple Classes of Antibiotics occurring forms new threat to human health along with the universal use of microbiotic in the whole world, the phenomenon of abuse of antibiotics is more prevalent for many years.At present, gram-positive microorganism and negative bacterium all have resistance trend, and the resistance problem of gram-positive microorganism is even more serious.Mycobacterium tuberculosis and the vancomycin-resistant enterococcus (VRE) of the methicillin resistant staphylococcus aureus (MRSA) occurring in world wide and staphylococcus epidermidis (MRSE), resistance streptococcus pneumoniae, multidrug resistance are the subject matter (Swartz of current clinical middle existence, M.N.Proc.Natl.Acad.Sci.U.S.A.1994,91,2420.).Especially the appearance of vancomycin-resistant enterococcus (VRE), has broken through " last resort " of severe infections patient treatment.
Oxazolidone has represented the novel complete synthesis antiseptic-germicide that a class is extremely promising, and the synthetic mechanism of action of its anti-bacteria early protein is different from known all microbiotic at present, means that the possibility of cross resistance appearance is less.The research emphasis of Xin mono-Dai oxazolidone medicine is intended to improve anti-microbial activity, and expansion antimicrobial spectrum, comprises the activity for Gram-negative bacteria.
summary of the invention
An object of the present invention is to provide novel oxazolidinone compound and the pharmacy acceptable salt thereof with anti-Multidrug resistant bacteria.
Another object of the present invention is to provide the preparation method of anti-Multidrug resistant bacteria novel oxazolidinone compound and salt thereof.
A further object of the present invention is to provide this compounds and salt thereof in the particularly application on the medicine of the microbial infection of multidrug resistance of preparation treatment infectious diseases.
The invention provides and have as shown in the formula (I) Jie Gou oxazolidinone compounds and salt thereof:
Figure A0215773500091
In formula, R represents or-NR 2r 3, wherein
R 1=can substituted alkyl sulphonyl, can substituted aryl sulfonyl, can substituted aromatic heterocycle alkylsulfonyl, can substituted amino acid formyl radical, can substituted aryl formyl radical, can substituted aryl-amino-carbonyl, can substituted arylamino thioformyl;
R 2=can substituted alkyl sulphonyl, can substituted aryl sulfonyl, can substituted aryl formyl radical, can substituted aromatic heterocycle formyl radical; With
R 3=H or alkyl.
The present invention also provides two kinds of preparation methods with above-mentioned formula (I) Jie Gou oxazolidinone compounds and salt thereof.
The first preparation method comprises the following steps:
(1) the fluoro-4-of (S)-N-[3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methyl] ethanamide and sulfonyl agent react 0.1-48 hour in-10～80 ℃ in non-polar solvent, obtains compound 1-9;
(2) compound 6-8 carries out catalytic hydrogenation and obtains compound 10-12 in polar solvent under metal catalyst exists;
(3) compound 10-12 carries out acetylization reaction 0.1-12 hour in-10～80 ℃ in non-polar solvent, obtains compound 13-15;
(4) aryl formic acid acyl chlorides and the fluoro-4-of (S)-N-[3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methyl] ethanamide obtains compound 16,17,18 for 0.1-48 hour in-10～80 ℃ of reactions in non-polar solvent; Or aryl formic acid or amino acid and N-hydroxy-succinamide (HOSU) or monohydroxy benzotriazole (HOBt) or dicyclohexyl carbodiimide (DCC) react, and then and the fluoro-4-of (S)-N-[3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methyl] ethanamide obtains compound 16 for 0.1-48 hour in-10～80 ℃ of reactions in non-polar solvent, 17,18;
(5) as required, be prepared into corresponding salt.
The second is preparation method comprise the following steps:
(1) (S)-N-[3-(the fluoro-4-aminophenyl of 3-)-2-oxo-5-oxazolidinyl methyl] ethanamide and sulfonyl agent react 0.1-48 hour in-10～80 ℃ in non-polar solvent, obtains compound 21-27;
(2) compound 26-27 carries out catalytic hydrogenation 8-24 hour in 0 ℃ in polar solvent under metal catalyst exists in room temperature range, obtains compound 28-29;
(3) compound 28-29 carries out acetylization reaction 0.1-12 hour in-10～80 ℃ in non-polar solvent, obtains compound 30-31;
(4) aryl formic acid acyl chlorides and the fluoro-4-of (S)-N-[3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methyl] ethanamide in-10～80 ℃ of reaction 0.1-48 hour, obtains compound 32-33 in non-polar solvent;
(5) as required, be prepared into corresponding salt.
The present invention further provides formula (I) and show that oxazolidinone compounds and salt thereof are in the particularly application on the medicine of the microbial infection of multidrug resistance of preparation treatment infectious diseases.
Describe the present invention below.
Unless dated especially, term used herein has as given a definition:
" alkyl " represents saturated or undersaturated, substituted or non-substituted straight chain, branched alkane hydrocarbon chain, can enumerate as methyl particularly, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, 1-methyl butyl, 2-methyl-propyl, hexyl, isohexyl, 1-methyl amyl, 2-methyl amyl, 3-methyl amyl, 2-methyl butyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethyl-butyl, 2-ethyl-butyl, 1, 1, 2-trimethylammonium propyl group, 1, 2, 2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl, 1-Ethyl-2-Methyl propyl group etc.In these groups, the alkyl that the carbonatomss such as methyl, ethyl, propyl group, sec.-propyl, butyl of take are 1-4, as good, for better, be take methyl, ethyl as best with methyl, ethyl and propyl group.
" aryl " represents aromatic hydrocarbyl, take the aryl of 6-14 carbon atom as good, is in particular phenyl, tolyl, xylyl, xenyl, naphthyl, indenyl, anthryl, phenanthryl, and better is phenyl or naphthyl, the best be phenyl.
" fragrant heterocyclic radical " represents to contain 1-4 heteroatomic five yuan or six membered heteroaryl that is selected from Sauerstoffatom, nitrogen-atoms or sulphur atom, furyl, thienyl, pyrryl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazyl etc.In these groups, take thienyl, furyl, oxazolyl, isoxazolyl and thiazolyl as good, better is that thienyl, oxazolyl is with isoxazolyl.
" can substituted alkyl ", " can substituted aryl " and " can substituted fragrant heterocyclic radical " represent that respectively above-mentioned " alkyl ", " aryl " and " fragrant heterocyclic radical " are optionally selected from halogen atom, alkyl, alkoxyl group, acyloxy ,-OH ,-NH 2, NO 2the group of ,-NHAc replaces.
The sulphonic acid anhydride that " sulfonyl agent " is selected from the SULPHURYL CHLORIDE that can be replaced by alkyl or aryl, the sulfuryl bromide that can be replaced by alkyl or aryl, can be replaced by alkyl or aryl.
" pharmacy acceptable salt " can be enumerated and hydrochloric acid particularly, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, the salt of the mineral acids such as phosphoric acid, with formic acid, acetic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, the organic acids such as ethyl sulfonic acid and aspartic acid, the acid salt of the acidic amino acids such as L-glutamic acid, or the salt forming with alkali, as sodium, potassium, calcium, the salt of the mineral alkalis such as aluminium, ammonium salt, methylamine salt, ethylamine salt, ethanolamine salt etc., or and Methionin, arginine, the salt that the basic aminoacidss such as ornithine form.
Oxazolidinone compounds of the present invention or its pharmacy acceptable salt can be made into the various preparations containing activeconstituents 0.01-99.9% (weight) and appropriate pharmaceutically acceptable carrier, as are suitable for the dosage form that oral, injection or enterally administering are used.
Can be according to curee's age (monthly age or week age), general health situation, disease severity and the course of disease, route of administration, individual the susceptibility of medicine etc. is used to the pharmaceutical preparation containing treatment significant quantity the compounds of this invention to curee.
(I) Suo Shi oxazolidinone compounds and salt thereof are prepared by following flow process formula of the present invention.
Flow process I
Figure A0215773500121
Illustration: a. alkyl or aryl SULPHURYL CHLORIDE, pyridine, 0～20 ℃; b.H 2/ Pd/C; C. diacetyl oxide, pyridine, 0～20 ℃; D. aryl formic acid or amino acid, HOSU or HOBt, DCC.
The embodiment of flow process I is listed below:
1. with 3,4-difluoro nitrobenzene is raw material, press currently known methods (Brickner, S.J.et al J.Med.Chem.1996,39,673-679) through the some step reaction fluoro-4-of synthetic intermediate (S)-N-3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methylacetamide.
2. the fluoro-4-of (S)-N-3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methylacetamide reacts 0.1-48 hour in-10～80 ℃ with SULPHURYL CHLORIDE in the non-polar solvents such as benzene, toluene, pyridine, methylene dichloride, chloroform, tetrahydrofuran (THF), top condition, for take pyridine as solvent is in 0～20 ℃ of reaction 8-24 hour, obtains compound 1-9.
3. to take methyl alcohol, ethanol, acetic acid etc. be solvent to compound 6-8, and take palladium/carbon or other is catalyzer containing palladium or nickeliferous metal catalyst, obtains compound 10-12 at normal temperatures and pressures through catalytic hydrogenation.The top condition of reaction is to take methyl alcohol as solvent, and palladium/carbon of 5% or 10% is catalyzer, catalytic hydrogenation under normal temperature and pressure.
4. compound 10-12 and acetic anhydride react 0.1-12 hour in-10～80 ℃ in the non-polar solvents such as benzene, toluene, pyridine, methylene dichloride, chloroform, tetrahydrofuran (THF), top condition, for take pyridine as solvent is in 0～20 ℃ of reaction 8-10 hour, obtains compound 13-15.
5. aryl formic acid acyl chlorides and the fluoro-4-of (S)-N-3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methylacetamide in the non-polar solvents such as benzene, toluene, pyridine, methylene dichloride, chloroform, tetrahydrofuran (THF) in-10～80 ℃ of reaction 0.1-48 hour, top condition 8-24 hour obtains compound 16 in 0～20 ℃ of reaction for take pyridine as solvent, 17,18; Or aryl formic acid or amino acid and N-hydroxy-succinamide (HOSU) or monohydroxy benzotriazole (HOBt) or dicyclohexyl carbodiimide (DCC) react, and then and the fluoro-4-of (S)-N-3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methylacetamide in dry tetrahydrofuran, methylene dichloride, chloroform, etc. in non-polar solvent in-10～80 ℃ of reaction 0.1-48 hour, top condition 8-24 hour obtains compound 16 in 0～20 ℃ of reaction for take pyridine as solvent, 17,18.
6. as required, be prepared into corresponding salt.
Flow process II
Illustration: a. alkyl or aryl SULPHURYL CHLORIDE, pyridine, 0～20 ℃; b.H 2/ Pd/C; C. diacetyl oxide, pyridine, 0～20 ℃; D. aryl acyl chlorides, pyridine, 0～20 ℃.
The embodiment of flow process II is listed below:
1. with 3,4-difluoro nitrobenzene is raw material, by currently known methods (Genin, M.J.et al J.Med.Chem.2000,43,953-970) through some step reaction synthetic intermediate (S)-N-3-(the fluoro-4-aminophenyl of 3-)-2-oxo-5-oxazolidinyl methylacetamides.
2. (S)-N-3-(the fluoro-4-aminophenyl of 3-)-2-oxo-5-oxazolidinyl methylacetamide reacts 0.1-48 hour in-10～80 ℃ with SULPHURYL CHLORIDE in the non-polar solvents such as benzene, toluene, pyridine, methylene dichloride, chloroform, tetrahydrofuran (THF), top condition, for take pyridine as solvent is in 0～20 ℃ of reaction 8-24 hour, obtains compound 21-27.
3. to take methyl alcohol, ethanol, acetic acid etc. be solvent to compound 26-27, with palladium/carbon or other palladium-containing catalyst, in 0 ℃, in room temperature range, react 8-24 hour, top condition is to take methyl alcohol as solvent, and palladium/carbon of 5% or 10% is that under catalyst normal temperature normal pressure, catalytic hydrogenation obtains compound 28-29.
4. compound 28-29 and acetic anhydride react 0.1-12 hour in-10～80 ℃ in the non-polar solvents such as benzene, toluene, pyridine, methylene dichloride, chloroform, tetrahydrofuran (THF), top condition, for take pyridine as solvent is in 0～20 ℃ of reaction 8-10 hour, obtains compound 30-31.
5. aryl formic acid acyl chlorides and the fluoro-4-of (S)-N-[3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methyl] ethanamide is in-10～80 ℃ of reaction 0.1-48 hour in the non-polar solvents such as benzene, toluene, pyridine, methylene dichloride, chloroform, tetrahydrofuran (THF), and top condition 8-24 hour obtains compound 32-33 in 0～20 ℃ of reaction for take pyridine as solvent.
6. as required, be prepared into corresponding salt.
Formula of the present invention (in I) Suo Shi oxazolidinone compounds, representative is following compound:
1. the fluoro-4-of (S)-N-3-[3-(4-methylsulfonyl-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
2. the fluoro-4-of (S)-N-3-[3-(4-benzenesulfonyl-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
3. the fluoro-4-[4-of (S)-N-3-[3-(4-Methyl benzenesulfonyl base)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
4. the fluoro-4-of (S)-N-3-[3-(4-anisole alkylsulfonyl-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
5. the fluoro-4-[4-of (S)-N-3-[3-(4-bromobenzenesulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
6. the fluoro-4-[4-of (S)-N-3-[3-(4-oil of mirbane alkylsulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
7. the fluoro-4-[4-of (S)-N-3-[3-(3-oil of mirbane alkylsulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
8. the fluoro-4-[4-of (S)-N-3-[3-(2-oil of mirbane alkylsulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
9. the fluoro-4-[4-of (S)-N-3-[3-(2-thiophen sulfuryl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
10. the fluoro-4-[4-of (S)-N-3-[3-(4-amino phenyl sulfonyl acyl group)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
The fluoro-4-[4-of 11. (S)-N-3-[3-(3-amino phenyl sulfonyl acyl group)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
The fluoro-4-[4-of 12. (S)-N-3-[3-(2-amino phenyl sulfonyl acyl group)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
The fluoro-4-[4-of 13. (S)-N-3-[3-(4-P-acetamido benzene sulfonyl base)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
The fluoro-4-[4-of 14. (S)-N-3-[3-(3-P-acetamido benzene sulfonyl base)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
The fluoro-4-[4-of 15. (S)-N-3-[3-(2-P-acetamido benzene sulfonyl base)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
The fluoro-4-[4-[3-of 16. (S)-N-3-[3-(the fluoro-6-chloro-phenyl-of 2-)-5-methyl-4-isoxazole formyl radical]-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
The fluoro-4-[4-of 17. (S)-N-3-[3-(2-hydroxy benzoyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
The fluoro-4-[4-of 18. (S)-N-3-[3-(L-phenylalanyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
The fluoro-4-[4-of 19. (S)-N-3-[3-(phenyl amino carbonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
The fluoro-4-[4-of 20. (S)-N-3-[3-(phenyl amino thiocarbonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
21. (S)-N-3-(the fluoro-4-methanesulfonamido of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
22. (S)-N-3-(the fluoro-4-phenylsulfonamido of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
23. (S)-N-3-(the fluoro-4-of 3-is to Methyl benzenesulfonyl aminophenyl)-2-oxo-5-oxazolidinyl methylacetamide;
24. (S)-N-3-(the fluoro-4-brosyl of 3-aminophenyl)-2-oxo-5-oxazolidinyl methylacetamide;
25. (S)-N-3-(the fluoro-4-of 3-is to anisole sulfonamido phenyl)--2-oxo-5-oxazolidinyl methylacetamide;
26. (S)-N-3-(the fluoro-4-p-nitrophenyl of 3-sulfonamido phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
27. (S)-N-3-(bromobenzene sulfonamido phenyl between the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methylacetamide;
28. (S)-N-3-(the fluoro-4-sulfanilamido of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
29. (S)-N-3-(the fluoro-4-metanilamido-of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
30. (S)-N-3-(the fluoro-4-acetparaminosalol of 3-phenylsulfonamido phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
31. (S)-N-3-(the fluoro-4-m-acetamino of 3-phenylsulfonamido phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
32. (S)-N-3-(the adjacent acetoxyl group phenylsulfonamido of the fluoro-4-of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
33. the fluoro-4-[3-of (S)-N-3-[3-(the fluoro-6-chloro-phenyl-of 2-)-5-methyl-4-cycliton base] phenyl]-2-oxo-5-oxazolidinyl methylacetamide.
The structural formula of above compound is in Table 1 and table 2.
Figure A0215773500161
Table 1
Numbering R 1
1??????????????????????CH 3SO 2
2??????????????????????PhSO 2
3??????????????????????4-CH 3.PhSO 2
4?????????????????????????????????4-CH 3O-PhSO 2
5?????????????????????????????????4-Br-PhSO 2
6?????????????????????????????????4-NO 2-PhSO 2
7?????????????????????????????????3-NO 2-PhSO 2
8?????????????????????????????????2-NO 2-PhSO 2
Figure A0215773500171
10????????????????????????????????4-NH 2-PhSO 2
11????????????????????????????????3-NH 2-PhSO 2
12????????????????????????????????2-NH 2-PhSO 2
13????????????????????????????????4-NHAc-PhSO 2
14????????????????????????????????3-NHAc-PhSO 2
15????????????????????????????????2-NHAc-PhSO 2
Figure A0215773500172
17????????????????????????????????2-OH-PhCO-
18????????????????????????????????L-PhCH 2CH 2(NH 2)CO-
19????????????????????????????????PhNHCO-
20????????????????????????????????PhNHCS-
Table 2
Numbering R 1r 3
21??????????????CH 3SO 2????????????H
22??????????????PhSO 2??????????????H
23??????????????4-CH 3-PhSO 2???????H
24??????????????4-Br-PhSO 2?????????H
25???????????????4-CH 3O-PhSO 2????????????????????????H
26???????????????4-NO 2-PhSO 2?????????????????????????H
27???????????????3-NO 2-PhSO 2?????????????????????????H
28???????????????4-NH 2-PhSO 2?????????????????????????H
29???????????????3-NH 2-PhSO 2?????????????????????????H
30???????????????4-NHAc-PhSO 2?????????????????????????H
31???????????????3-NHAc-PhSO 2?????????????????????????H
32???????????????2-AcO-PhSO 2??????????????????????????H
33??????????????
Antibacterial activity in vitro is measured:
1. test method: adopt agar doubling dilution to measure compound to the minimum inhibitory concentration of strain subject (MIC).Draw respectively test-compound 1ml and add in sterilizing plate, then in plate, add 19mlM-H nutrient agar (being melted up to 50 ℃), making the final concentration of contained compound in each plate is 128,64,32,16,8,4,2,1,0.5,0.25 μ g/ml, then with multiple spot, inoculate instrument (Denley A400) in each plate surface seeding bacterium respectively, bacterium liquid final concentration is 1O 5cFU/ml.Insert in 37 ℃ and cultivate 20 hours, observations, the minimum inhibitory concentration (MIC) that the minimum concentration of take without medicine in bacterial growth plate is this bacterium.
2. test strain: test strain used is the clinical separated pathogenic bacterium that calendar year 2001 collects in Sichuan province, uses after ordinary method is identified again.Test-compound CH 3after OH or DMSO hydrotropy, the mother liquor that is configured to 2560 μ g/ml with sterile purified water is standby.
3. positive controls is Linezolid.
4. the MIC of each compound 50, MIC 90value is in Table 3.In 33 test-compounds 1,2,4,7,10,11,13,17,19,20,32 pairs of trial 20 strain gram-positive microorganisms all have better antibacterial activity as shown in Table 3, and 11 activity is better than positive control Linezolid.The related oxazolidinone derivative of the present invention can be used for the treatment of the infection that gram-positive microorganism causes.
The antibacterial activity in vitro of 33 compounds of table 3 to gram positive organism
Bacterium
1????2??????3???????4??????5????????6??????7??????10????11????13??????14???????16????????17??????18????19
Streptococcus pneumoniae 01,181 22 > 128 8 > 128 128 1 16 1 32 > 128 > 128 8 64 16
Non-ABD suis 01,121 22 64 4 > 128 64 0.5 21 32 > 128 > 128 8 64 16
A suis 991 22 128 2 > 128 64 1 16 18 > 128 > 128 4 64 16
D suis 992 44 128 16 > 128 > 128 4 16 1 32 > 128 > 128 4 64 16
Hemolytic Portugal coccus 011,925 21 64 2 > 128 32 0.5 0.25 0.25 4 > 128 > 128 8 32 8
Hemolytic Portugal coccus 011,926 2 0.5 4 0.5 > 128 16 0.25 0.25 0.25 1 > 128 > 128 4 32 8
Staphylococcus aureus ATCC25923 44 128 2 > 128 128 2 16 0.5 32 > 128 > 128 4 64 16
Staphylococcus aureus 01,193 44 128 16 > 128 > 128 4 16 0.5 32 > 128 > 128 4 64 16
Staphylococcus aureus 01,194 2182 > 128 64 0.25 0.25 0.25 2 > 128 > 128 4 16 4
Staphylococcus aureus 011,910 44 128 4 > 128 128 11 0.5 32 > 128 > 128 4 64 8
Staphylococcus aureus 011,911 44 128 4 > 128 128 18 0.5 32 > 128 > 128 4 64 8
Staphylococcus aureus 011,912 44 128 4 > 128 128 18 0.5 16 > 128 > 128 4 64 4
Staphylococcus aureus 011,915 1 0.5 8 0.5 > 128 4 0.25 0.25 0.25 1 > 128 > 128 2 16 1
Staphylococcus aureus 011,916 44 128 8 > 128 128 11 0.5 16 > 128 > 128 4 64 16
Table coccus 01,206 0.5 0.25 2 0.5 128 4 0.25 0.25 0.25 1 > 128 > 128 281 of Portugal
Table coccus 01,207 0.5 0.25 2 0.25 128 8 0.25 0.25 0.25 0.5 > 128 > 128 48 0.5 of Portugal
Table coccus 01,208 0.5 0.25 2 0.25 128 8 0.25 0.25 0.25 1 > 128 > 128 482 of Portugal
Table coccus 012,010 0.5 0.25 4 0.5 128 8 0.25 0.25 0.25 0.5 > 128 > 128 2 16 1 of Portugal
Table coccus 012011 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 of Portugal
Table coccus 012013 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 of Portugal
The antibacterial activity in vitro comparison of 3 33 compounds of continued to gram positive organism
Bacterium
20????21?????22?????23?????24??????25?????26??????27??????28??????29??????30??????31????32?????33?????LZ
Streptococcus pneumoniae 01,181 8 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 128 8 > 128 2
Non-ABD suis 01,121 2 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 16 > 128 64 0.5 > 128 2
A suis 991 8 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 128 > 128 64 0.5 > 128 1
D suis 992 8 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 128 > 128 128 1 > 128 2
Hemolytic Portugal coccus 011,925 2 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 64 0.25 > 128 1
Hemolytic Portugal coccus 011,926 0.5 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 16 0.25 > 128 0.25
Staphylococcus aureus ATCC25923 2 28 > 128 > 128 > 128 > 128 > 128 > 128 > 128 16 > 128 64 1 > 128 2
Staphylococcus aureus 01,193 2 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 128 4 > 128 2
Staphylococcus aureus 01,194 2 64 > 128 > 128 > 128 128 > 128 > 128 > 128 > 128 > 128 64 0.5 > 128 0.5
Staphylococcus aureus 011,910 8 128 > 128 > 128 > 128 128 > 128 > 128 > 128 128 > 128 64 1 > 128 0.5
Staphylococcus aureus 011,911 8 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 64 > 128 128 2 > 128 0.5
Staphylococcus aureus 011,912 2 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 64 > 128 128 8 > 128 1
Staphylococcus aureus 011,915 2 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 64 > 0.25 > 128 0.5
Staphylococcus aureus 011,916 2 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 64 0.5 > 128 1
Table coccus 01,206 1 64 > 128 > 128 > 128 128 > 128 > 128 > 128 > 128 > 128 32 0.25 > 128 0.25 of Portugal
Table coccus 01,207 0.5 64 > 128 > 128 > 128 > 128 > 128 > 128 128 32 > 128 16 0.25 > 128 0.25 of Portugal
Table coccus 01,208 0.5 64 64 > 128 > 128 128 > 128 > 128 > 128 2 > 128 32 4 > 128 0.25 of Portugal
Table coccus 012,010 0.5 64 64 > 128 > 128 128 > 128 > 128 > 128 0.25 > 128 32 0.5 > 128 0.5 of Portugal
Table coccus 012011 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 128 of Portugal
Table coccus 012013 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 32 of Portugal
LZ=linezolid
embodiment
Below in conjunction with embodiment, the present invention is further elaborated, but these embodiment are never any limitation of the invention.In all embodiment, fusing point is measured with MEL-TEMP melting point apparatus, and thermometer is not proofreaied and correct; 1varian Mercury 400 nuclear magnetic resonance analyser records for H-NMR, chemical shift represents with δ (ppm); Separated with the undeclared 200-300 order that is of silica gel.
Embodiment 1:(S) the fluoro-4-of-N-3-[3-(4-methylsulfonyl-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methylacetamide (1)
(S) the fluoro-4-of-N-3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methylacetamide (177.0mg, 0.53mmol) be suspended in 5ml pyridine, stir and frozen water cooling under, add methylsulfonyl chloride (1.0ml, 1.28mmol), temperature of reaction slowly rises to room temperature and reacts and spend the night.After methylene dichloride for reaction mixture (20.0mL) dilution, successively with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated common salt washing, anhydrous sodium sulfate drying, filter, filtrate is concentrated, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=20: 1), obtain white solid title compound 53.0mg, yield 24.2%.Fusing point: 209.5-211 ℃. 1H-NMR(CDCl 3)：δ8.40(t，1H)，7.89(dd，1H)，7.35(dd，1H)，7.18(dd，1H)，7.12(dd，1H)，6.00(m，1H)，4.80(m，1H)，3.94-4.10(m，13H)，3.58-3.84(m，6H)，3.28-3.40(m，3H)，3.25(brs，3H)，2.03(s，3H)。
Embodiment 2:(S) the fluoro-4-of-N-3-[3-(4-benzenesulfonyl-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methylacetamide (2)
Operation steps is similar to the synthetic of compound 1, obtains white solid title compound 189.0mg, yield 82.9%.Fusing point: 191-193 ℃. 1H-NMR(CDCl 3)：δ?7.75(d，2H)，7.63(m，1H)，7.58(dd，1H)，7.42(dd，1H)，7.02(dd，1H)，6.95(t，1H)，6.08(m，1H)，4.74(m，1H)，3.98(t，1H)，3.55-3.75(m，3H)，3.20(brs，4H)，3.10(brs，4H)，1.98(s，3H)。
Embodiment 3:(S) the fluoro-4-[4-of-N-3-[3-(4-Methyl benzenesulfonyl base)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (3)
Operation steps is similar to the synthetic of compound 1, obtains white solid title compound 169.0mg, yield 69.0%.Fusing point: 224-227 ℃. 1H-NMR(CDCl 3)：δ7.65(d，2H)，7.45(dd，1H)，7.35(d，2H)，6.95-7.05(m，2H)，6.15(m，1H)，4.75(m，1H)，(4.00(t，1H)，3.56-3.76(m，3H)，3.12-3.22(m，8H)，2.18(s，3H)，2.00(s，3H)。
Embodiment 4:(S) the fluoro-4-[4-of-N-3-[3-(4-methoxy benzenesulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (4)
Operation steps is similar to the synthetic of compound 1, obtains white solid title compound 210.0mg, yield 83.0%.230 ℃ of fusing point: >. 1H-NMR(CDCl 3)：δ8.37(t，1H)，7.86(dd，1H)，7.70-7.75(m，2H)，7.30(dd，1H)，7.01-7.10(m，3H)，6.15(m，1H)，4.80(m，1H)，3.86-4.10(m，3H)，3.56-3.84(m，8H)，3.20(brs，3H)，2.00(s，3H)。
Embodiment 5:(S) the fluoro-4-[4-of-N-3-[3-(4-bromobenzenesulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (5)
Operation steps is similar to the synthetic of compound 1, obtains white solid title compound 210.0mg, yield 75.7%.Fusing point: 203-205 ℃. 1H-NMR(CDCl 3)：δ?7.60-7.73(m，7H)，7.06(dd，1H)，
6.16(t，1H)，4.80(m，1H)，4.00(m，3H)，3.40-3.50(m，7H)，3.30(brs，1H)，2.00(s，3H)。
Embodiment 6:(S) the fluoro-4-[4-of-N-3-[3-(4-oil of mirbane alkylsulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (6)
Operation steps is similar to the synthetic of compound 1, obtains yellow solid title compound 590.0mg, yield 56.6%.Fusing point: 188-190 ℃. 1H-NMR(DMSO)：δ8.20(d，2H)，7.95(d，2H)，7.45(dd，2H)，6.94-7.05(m，2H)，6.03(t，1H)，4.74(m，1H)，3.56-3.84(m，3H)，3.26(brs，4H)，3.15(brs，4H)，2.00(s，3H)。
Embodiment 7:(S) the fluoro-4-[4-of-N-3-[3-(3-oil of mirbane alkylsulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (7)
Operation steps is similar to the synthetic of compound 1, obtains yellow solid title compound 511.0mg, yield 63.0%.Fusing point: 175-178 ℃. 1H-NMR(CDCl 3)：δ8.63(t，1H)，8.50(m，21H)，8.15(m，1H)，7.80(t，1H)，7.45(dd，1H)，7.98-8.04(m，2H)，6.10(t，1H)，4.76(m，1H)，4.00(t，1H)，3.60-3.85(m，3H)，3.30(brs，4H)，3.18(brs，4H)，2.00(s，3H)。
Embodiment 8:(S) the fluoro-4-[4-of-N-3-[3-(2-oil of mirbane alkylsulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (8)
Operation steps is similar to the synthetic of compound 1, obtains yellow solid title compound 355.0mg, yield 52.4%.62 ℃ of fusing point: 158-1. 1H-NMR(DMSO)：δ7.99-8.04(m，2H)，7.85-7.95(m，2H)，7.47(dd，1H)，7.15(dd，1H)，7.06(t，1H)，4.69(m，1H)，4.05(t，1H)，3.68(q，1H)，3.39(m，2H)，3.04(brs，4H)，1.80(s，3H)。
Embodiment 9:(S) the fluoro-4-[4-of-N-3-[3-(2-thiophen sulfuryl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (9)
Operation steps is similar to the synthetic of compound 1, obtains white solid title compound 156.0mg, yield 85.0%.Fusing point: 202-205 ℃. 1H-NMR(CDCl 3)：δ7.63(dd，1H)，7.55(dd，1H)，43(dd，1H)，7.15(q，1H)，7.03(dd，1H)，6.93(t，1H)，6.10(t，1H)，4.74(m，1H)，3.98(t，1H)，3.54-3.74(m，3H)，3.23(m，4H)，3.14(m，4H)，2.00(s，3H)。
Embodiment 10:(S) the fluoro-4-[4-of-N-3-[3-(4-amino phenyl sulfonyl acyl group)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (10)
Compound 6 (490.0mg 0.94mmol) is dissolved in the mixed solution of methyl alcohol (30.0mL) and methylene dichloride (30mL), adds 5% palladium carbon (65.0mg), and catalytic hydrogenation is spent the night at normal temperatures and pressures.Filter out catalyzer, concentrating under reduced pressure solvent, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=20: 1) obtain white solid title compound 420.0mg, yield 91.0%.
230 ℃ of fusing point: >. 1H-NMR(DMSO)：δ8.20(t，1H)，7.40-7.45(m，3H)，7.00-7.15(m，2H)，6.65(d，2H)，4.70(m，1H)，4.04(m，1H)，3.66(q，1H)，3.30(brs，5H)，2.93-3.00(m，8H)，1.80(s，3H)。
Embodiment 11:(S) the fluoro-4-[4-of-N-3-[3-(3-amino phenyl sulfonyl acyl group)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (11)
Operation steps is similar to the synthetic of compound 10, obtains white solid title compound 312.0mg, yield 80.7%.Fusing point: 206-210 ℃. 1H-NMR(DMSO)：δ8.20(t，1H)，7.45(dd，1H)，7.25(t，1H)，7.14(dd，1H)，7.04(t，1H)，6.92(t，1H)，6.79-6.85(m，2H)，4.68(m，1H)，4.04(t，1H)，3.65(m，1H)，3.00(m，10H)，1.80(s，3H)。
Embodiment 12:(S) the fluoro-4-[4-of-N-3-[3-(2-amino phenyl sulfonyl acyl group)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (12)
Operation steps is similar to the synthetic of compound 10,, obtain white solid title compound 111.0mg, yield 43.5%.230 ℃ of fusing point: >. 1H-NMR(CDCl 3)：δ7.58(d，1H)，7.46(dd，1H)，7.32(t，1H)，6.95-7.06(m，2H)，6.75-6.80(m，2H)，6.05(brs，1H)，4.75(brs，1H)，4.00(t，1H)，3.58-3.76(m，3H)，3.30(brs，4H)，3.12(brs，4H)，2.00(s，3H)。
Embodiment 13:(S) the fluoro-4-[4-of-N-3-[3-(4-P-acetamido benzene sulfonyl base)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (13)
Compound 10 (2720.mg 0.56mmol) is dissolved in pyridine (10.0mL), at frozen water cooling and stir under, be added dropwise to diacetyl oxide (1.0mL), stirring is spent the night.Reaction mixture dilutes with methylene dichloride, uses successively 1N hydrochloric acid, water, saturated sodium bicarbonate solution, saturated common salt washing, anhydrous sodium sulfate drying.Filter, filtrate is concentrated, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=12: 1) obtain beige solid title compound 196.0mg, yield 66%.Fusing point: 228-230 ℃. 1H-NMR(DMSO)：δ8.20(t，1H)，7.84(d，2H)，7.70(d，2H)，7.45(dd，1H)，7.15(dd，1H)，7.04(t，1H)，4.68(m，1H)，4.04(t，1H)，3.00(m，8H)，2.08(s，3H)，1.80(s，3H)。
Embodiment 14:(S) the fluoro-4-[4-of-N-3-[3-(3-P-acetamido benzene sulfonyl base)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (14)
Operation steps is similar to the synthetic of compound 13, obtains colorless solid title compound 31.0mg, yield 27.7%.Fusing point: 222-225 ℃. 1H-NMR(DMSO)：610.35(s，1H)，8.09(s，1H)，7.85(d，1H)，7.58(t，1H)，7.00-7.15(m，2H)，7.14(dd，1H)，7.04(t，1H)，4.70(m，1H)，4.04(t，1H)，3.65(q，3H)，3.00(m，10H)2.06(s，3H)，1.80(s，3H)。
Embodiment 15:(S) the fluoro-4-[4-of-N-3-[3-(2-P-acetamido benzene sulfonyl base)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (15)
Operation steps is similar to the synthetic of compound 13, obtains yellow solid title compound 15.5mg.Yield 30.0.7%.Fusing point: 156-158 ℃. 1H-NMR(DMSO)：δ9.57(s，1H)，8.07(dd，1H)，7.71-7.77(m，1H)，7.58-7.64(m，1H)，7.21-7.31(m，1H)，7.06-7.09(m，1H)，6.88-6.98(m，1H)，4.82(m，1H)，4.18(d×t，1H)，4.08(m，1H)，3.86(m，1H)，3.70(m，1H)，3.36(m，2H)，3.25(m，2H)，3.10(m，4H)，2.35(s，3H)，2.20(s，3H)。
Embodiment 16:(S) the fluoro-4-[4-[3-of-N-3-[3-(the fluoro-6-chloro-phenyl-of 2-)-5-methyl-4-isoxazole formyl radical]-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (16)
5-methyl-4-(the fluoro-6-chloro-phenyl-of 2-) 4-isoxazole acid (422.0mg, 1.65mmol) is dissolved in dry tetrahydrofuran (10mL), drips sulfur oxychloride (0.5mL) under stirring at room, and reaction mixture reflux is spent the night.Concentrating under reduced pressure solvent obtains a red liquid (stand-by).The fluoro-4-of compound (S)-N-[3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methyl] ethanamide (52.0mg, 0.17mmol) be suspended in pyridine (8mL), frozen water cooling and stir under, drip above-mentioned red liquid, after four hours, raw material point is basic disappears.Reaction mixture dilutes by ethyl acetate, uses successively 1N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated common salt washing, anhydrous sodium sulfate drying.Filter, filtrate is concentrated, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=20: 1) obtain light yellow solid 47.0mg, re-crystallizing in ethyl acetate obtains white solid title compound 17.0mg, two step total recoverys 20%.Fusing point: 218-220 ℃. 1H-NMR(DMSO)：δ7.59-7.65(m，1H)，7.41-7.54(m，3H)，7.18(dd，1H)，7.00(t，1H)，4.70(m，1H)，4.07(t，1H)，3.70(q，1H)，3.44-3.62(brs，3H)，3.40(m，3H)，2.74-2.90(brs，2H)，3.10(m，4H)，2.58(s，3H)，1.83(s，3H)。
Embodiment 17:(S) the fluoro-4-[4-of-N-3-[3-(2-hydroxy benzoyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (17)
2 hydroxybenzoic acid (46.0mg, 0.36mmol) be dissolved in dry tetrahydrofuran (10mL), frozen water cooling and stir under, add HOSU (37.0mg) and DCC (60.0mg), reaction adds the fluoro-4-of compound (S)-N-[3-[3-(1-piperazinyl) phenyl after spending the night]-2-oxo-5-oxazolidinyl methyl] ethanamide (65.0mg, 0.19mmol), continuing reaction spends the night.Reaction mixture filters, and filtrate is concentrated, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=10: 1) obtain white solid title compound 20.0mg, yield 23.0%.Fusing point: 159-162 ℃. 1H-NMR(DMSO)：δ8.23(t，1H)，7.47(dd，1H)，7.02-7.25(m，4H)，6.85(m，2H)，4.68(m，1H)，4.06(t，1H)，3.70(m，2H)，3.40(m，3H)，2.95(brs，4H)，1.83(s，3H)。
The fluoro-4-[4-of embodiment 18 (S)-N-3-[3-(L-phenylalanyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (18)
The L-Phe (126.0mg 0.46mmol) of BOC protection is dissolved in dry tetrahydrofuran (10mL); frozen water cooling and stir under; add HOBt (90.0mg); after one hour, add DCC (130.0mg) and the fluoro-4-of compound (S)-N-[3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methyl] ethanamide (167.0mg; 0.50mmol), reaction is spent the night.Ethyl acetate diluted reaction mixture, water and saturated common salt washing successively, anhydrous sodium sulfate drying.Filter, filtrate is concentrated, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=20: 1) obtain yellow oil 285mg.Above-mentioned yellow oil is dissolved in methylene dichloride (6.0mL), under stirring at room, adds trifluoracetic acid (3.8mL), after half an hour, TLC detects the basic disappearance of raw material point, concentrated solvent, and residue dissolves with methylene dichloride, saturated common salt washing, anhydrous sodium sulfate drying.Filter, filtrate is concentrated, and residue column chromatography for separation (methyl alcohol) obtains white solid title compound 133.0mg, two step total recoverys 55.0%.Fusing point: 152-154 ℃. 1H-NMR(DMSO)：δ8.22(t，1H)，7.48(dd，1H)，7.14-7.28(m，6H)，6.94(t，1H)，4.68(m，1H)，4.05(t，1H)，3.95(t，1H)，3.60-3.70(m，2H)，3.40-3.55(m，2H)，2.60-3.00(m，6H)，1.83(s，3H)。
Embodiment 19:(S) the fluoro-4-[4-of-N-3-[3-(phenyl amino carbonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (19)
The fluoro-4-of compound (S)-N-[3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methyl] ethanamide (62.0mg, 0.18mmol) be dissolved in methyl alcohol (5.0mL), under stirring at room, drip phenylcarbimide (0.12mL, 1.1mmol) and triethylamine (0.1mL), reaction is spent the night.TLC detects raw material point and disappears, and filters the solid generating, and solid, at air drying, obtains white solid title compound 20.0mg, yield 26%.230 ℃ of fusing point: >. 1H-NMR(DMSO)：δ8.40(s，1H)，8.23(t，1H)，7.50(d，1H)，7.43-7.48(m，1H)，7.15-7.24(m，2H)，7.09(t，1H)，6.92(t，1H)，4.70(m，1H)，4.0?7(t，1H)3.69(q，1H)，3.60(m，3H)，3.40(t，2H)，2.97(m，4H)，1.80(s，3H)。
Embodiment 20:(S) the fluoro-4-[4-of-N-3-[3-(phenyl amino thiocarbonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (20)
Operation steps is similar to the synthetic of compound 19, obtains pale solid title compound 22.0mg, yield 22%.Fusing point: 218-220 ℃. 1H-NMR(DMSO)：δ7.50(dd，1H)，7.27-7.7.30(m，4H)，7.18(dd，1H)，7.08-7.12(m，2H)，4.70(m，1H)，4.05(m，5H)，3.70(m，1H)，3.40(m，2H)，3.02(m，4H)，1.80(s，3H)。
Embodiment 21:(S)-N-3-(the fluoro-4-methanesulfonamido of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide (21)
(S)-N-3-(the fluoro-4-aminophenyl of 3-)-2-oxo-5-oxazolidinyl methylacetamide of take is raw material, and other operation steps is similar to the synthetic of compound 1.Obtain white solid title compound 54.0mg, yield 41.8%.Fusing point: 223-224 ℃. 1H-NMR(CDCl 3)：δ7.70(dd，1H)，7.35(t，1H)，6.03(m，1H)，4.80(m，1H)，4.05(t，1H)，3.80(q，1H)，3.68(m，2H)，3.43(s，3H)，2.04(s，3H)。
Embodiment 22:(S)-N-3-(the fluoro-4-phenylsulfonamido of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide (22)
Operation steps is similar to the synthetic of compound 21, obtains white solid title compound 91.0mg, yield 55.0%.230 ℃ of fusing point: >. 1H-NMR(CDCl 3)：δ7.95(dd，2H)，7.68(t，1H)，7.51-7.58(m，3H)，7.20(m，1H)，7.09(t，1H)，7.20(d，2H)，6.00(brs，1H)，4.79(m，1H)，4.05(t，1H)，3.60-3.80(m，3H)，2.04(s，3H)。
Embodiment 23:(S)-N-3-(the fluoro-4-of 3-is to Methyl benzenesulfonyl aminophenyl)-2-oxo-5-oxazolidinyl methylacetamide (23)
Operation steps is similar to the synthetic of compound 21, obtains white solid title compound 54.0mg, yield 64.0%.Fusing point: 202-204 ℃. 1H-NMR(CDCl 3)：δ7.60(d，2H)，7.55(t，1H)，7.47(dd，1H)，7.20(d，2H)，6.99(m，1H)，6.65(brs，1H)，6.00(t，1H)，4.74(m，1H)，3.98(t，1H)，3.54-3.74(m，3H)，2.37(s，3H)，2.00(s，3H)。
Embodiment 24:(S)-N-3-(the fluoro-4-brosyl of 3-aminophenyl)-2-oxo-5-oxazolidinyl methylacetamide (24)
Operation steps is similar to the synthetic of compound 21.Obtain yellowish red color solid title compound 170.0mg, yield 85.0%.230 ℃ of fusing point: >. 1H-NMR(CDCl 3)：δ7.78(dd，2H)，7.68(dd，2H)，7.56(dd，1H)，7.20(m，1H)，7.05(t，1H)，6.00(t，1H)，4.79(brs，1H)，4.05(t，1H)，3.79(t，1H)，3.60-3.70(m，2H)，2.03(s，3H)。
Embodiment 25:(S)-N-3-(the fluoro-4-of 3-is to anisole sulfonamido phenyl)-2-oxo-5-oxazolidinyl methylacetamide (25)
Operation steps is similar to the synthetic of compound 21, obtains white solid title compound 224.0mg, yield 77.0%.230 ℃ of fusing point: >. 1H-NMR(CDCl 3)：δ7.83-7.88(m，2H)，7.54(dd，1H)，7.18(d，1H)，7.07(t，1H)，6.96-7.00(m，2H)，6.03(brs，1H)，4.79(brs，1H)，4.04(t，1H)，3.88(s，3H)，3.78(t，1H)，3.60-3.68(m，2H)，2.03(s，3H)。
Embodiment 26:(S)-N-3-(the fluoro-4-p-nitrophenyl of 3-sulfonamido phenyl)-2-oxo-5-oxazolidinyl methylacetamide (26)
Operation steps is similar to the synthetic of compound 21, obtains yellow solid title compound 303.0mg, yield 30.0%.Fusing point: 218-222 ℃. 1H-NMR(CDCl 3)：δ8.29(d，2H)，7.92(d，2H)，7.59(t，1H)，7.50(dd，1H)，7.10(d，1H)，6.77(brs?1H)，5.96(brs，1H)，4.79(m，1H)，4.00(t，1H)，3.65-3.80(m，2H)，3.60(m，1H)，2.00(s，3H)。
Embodiment 27:(S)-N-3-(bromobenzene sulfonamido phenyl between the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methylacetamide (27)
Operation steps is similar to the synthetic of compound 21, obtains light yellow solid title compound 683.0mg, yield 72.0%.Fusing point: 210-214 ℃. 1H-NMR(CDCl 3)：δ8.56(t，1H)，8.38-8.42(m，1H)，8.03-8.06(m，1H)，7.67(q，1H)，7.58(t，1H)，7.49(dd，1H)，7.08(m，1H)，6.92(brs，1H)，6.00(brs，1H)，4.79(m，1H)，4.00(t，1H)，3.60-3.80(m，3H)，2.00(s，3H)。
Embodiment 28:(S)-N-3-(the fluoro-4-sulfanilamido of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide (28)
Compound 26 (200.mg, 0.44mmol) is dissolved in methyl alcohol (50.0mL), adds 5% palladium carbon (50.0mg), and at room temperature catalytic hydrogenation is spent the night.Filter out catalyzer, concentrating under reduced pressure solvent, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=20:1) obtain white solid title compound 106.0mg, yield 60%. fusing points: 189-194 ℃. 1h-NMR (CDCl 3) 7.50-8.20 (m, 3H), 7.20-7.40 (m, 2H), 7.00 (brs, 1H), 4.65 (brs, 2H), 3.94 (m, 1H), 3.69 (brs, 1H), 1.80 (s, 3H).
Embodiment 29:(S)-N-3-(the fluoro-4-metanilamido-of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide (29)
Operation steps is similar to the synthetic of compound 21, obtains white solid title compound 100.0mg, yield 20.0%. fusing point: 218-222 ℃. 1h-NMR (DMSO): δ 8.22 (d, 1H), 7.44 (d, 1H), 7.10-7.20 (m, 3H), 6.88 (brs, 1H), 6.69-6.78 (m, 2H), 5.74 (s, 1H), 4.68 (brs, 1H), 3.04 (t, 1H), 3.69 (m, 1H), 1.80 (s, 3H).
Embodiment 30:(S)-N-3-(the fluoro-4-acetparaminosalol of 3-phenylsulfonamido phenyl)-2-oxo-5-oxazolidinyl methylacetamide (30)
Compound 28 (70.0mg, 0.18mmol) is dissolved in pyridine (5.0mL), frozen water cooling and stir under, drip diacetyl oxide (1.0mL), reaction is spent the night.Reaction mixture dilutes with methylene dichloride, uses successively 1N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated common salt washing, anhydrous sodium sulfate drying.Filter, filtrate is concentrated, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=12:1) obtain white solid title compound 78.0mg, yield 90.0%.230 ℃ of fusing point >. 1H-NMR(DMSO)：δ10.45(s，1H)，8.25(t，1H)，7.85(d×t，4H)，7.70(dd，1H)，7.56(t，1H)，7.45(dd，1H)，4.68(m，1H)，4.19(t，1H)，3.80(m，1H)，3.42(m，2H)，2.09(s，3H)，1.83(s，3H)。
Embodiment 31:(S)-N-3-(the fluoro-4-m-acetamino of 3-phenylsulfonamido phenyl)-2-oxo-5-oxazolidinyl methylacetamide (31)
Operation steps is similar to the synthetic of compound 30, obtains white solid title compound 24.0mg, yield 42.0%.230 ℃ of fusing point >. 1H-NMR(DMSO)：δ10.37(s，1H)，8.29(brs，1H)，8.25(t，1H)，7.90(dd，1H)，7.75(dd，1H)，7.59(m，3H)，7.45(dd，1H)，4.76(m，1H)，4.19(t，1H)，4.05(q，1H)，3.79(q，1H)，3.42(m，2H)，2.07(s，3H)，1.83(s，3H)。
Embodiment 32:(S)-N-3-(the adjacent acetoxyl group phenylsulfonamido of the fluoro-4-of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide (32)
Compound (S)-N-3-(the fluoro-4-aminophenyl of 3-)-2-oxo-5-oxazolidinyl methylacetamide (59.0mg, 0.221mmol) be dissolved in (8.0mL) in dry tetrahydrofuran, frozen water cooling and stir under, drip 2-acetyl oxygen Benzoyl chloride (0.70mL) and 3 triethylamines, reaction is spent the night.Ethyl acetate diluted reaction mixture, uses 1N hydrochloric acid successively, water, saturated sodium bicarbonate solution, saturated common salt washing, anhydrous sodium sulfate drying.Filter, filtrate is concentrated, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=25: 1) obtain white solid title compound 23.0mg, yield 24.0%.Fusing point: 220-222 ℃. 1H-NMR(DMSO)：δ10.03(s，1H)，7.70(d，1H)，7.60(m，3H)，7.38(t，1H)，7.25(m，2H)，4.73(m，1H)，4.10(t，1H)，3.73(m，1H)，3.40(m，2H)，2.20(s，3H)，1.82(s，3H)。
Embodiment 33:(S) the fluoro-4-[3-of-N-3-[3-(the fluoro-6-chloro-phenyl-of 2-)-5-methyl-4-cycliton base] phenyl]-2-oxo-5-oxazolidinyl methylacetamide (33)
Compound (S)-N-3-(the fluoro-4-aminophenyl of 3-)-2-oxo-5-oxazolidinyl methylacetamide (53.0mg 0.20mmol) is dissolved in pyridine (8.0mL), frozen water cooling and stir under, drip 5-methyl-4-(the fluoro-6-chloro-phenyl-of 2-) 4-isoxazole formyl chloride (453.4mg, 1.665mmol).After two hours, TLC detects the basic disappearance of raw material point, uses ethyl acetate diluted reaction mixture, uses successively 1N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated common salt washing, anhydrous sodium sulfate drying.Filter, filtrate is concentrated, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=25: 1) obtain white solid title compound 97.0mg, yield 97.0%.Fusing point: 181-184 ℃. 1H-NMR(DMSO)：δ?8.23(t，1H)，7.50-7.7.60(m，3H)，7.48(d，1H)，7.38(m，1H)，7.25(d，1H)，4.70(m，1H)，4.08(t，1H)，3.70(q，1H)，2.72(s，3H)，1.83(s，3H)。

Claims (13)

  1. As shown in the formula (I) Suo Shi oxazolidinone compounds or its pharmacy acceptable salt:
    In formula, R represents
    Figure A0215773500022
    or-NR 2r 3, wherein
    R 1=can substituted alkyl sulphonyl, can substituted aryl sulfonyl, can substituted aromatic heterocycle alkylsulfonyl, can substituted amino acid formyl radical, can substituted aryl formyl radical, can substituted aryl-amino-carbonyl, can substituted arylamino thioformyl;
    R 2=can substituted alkyl sulphonyl, can substituted aryl sulfonyl, can substituted aryl formyl radical, can substituted aromatic heterocycle formyl radical;
    R 3=H or alkyl.
  2. 2. compound as claimed in claim 1 or its pharmacy acceptable salt, wherein said compound is:
    (1) the fluoro-4-of (S)-N-3-[3-(4-methylsulfonyl-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (2) the fluoro-4-of (S)-N-3-[3-(4-benzenesulfonyl-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (3) the fluoro-4-[4-of (S)-N-3-[3-(4-Methyl benzenesulfonyl base)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (4) the fluoro-4-of (S)-N-3-[3-(4-anisole alkylsulfonyl-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (5) the fluoro-4-[4-of (S)-N-3-[3-(4-bromobenzenesulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (6) the fluoro-4-[4-of (S)-N-3-[3-(4-oil of mirbane alkylsulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (7) the fluoro-4-[4-of (S)-N-3-[3-(3-oil of mirbane alkylsulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (8) the fluoro-4-[4-of (S)-N-3-[3-(2-oil of mirbane alkylsulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (9) the fluoro-4-[4-of (S)-N-3-[3-(2-thiophen sulfuryl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (10) the fluoro-4-[4-of (S)-N-3-[3-(4-amino phenyl sulfonyl acyl group)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (11) the fluoro-4-[4-of (S)-N-3-[3-(3-amino phenyl sulfonyl acyl group)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (12) the fluoro-4-[4-of (S)-N-3-[3-(2-amino phenyl sulfonyl acyl group)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (13) the fluoro-4-[4-of (S)-N-3-[3-(4-P-acetamido benzene sulfonyl base)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (14) the fluoro-4-[4-of (S)-N-3-[3-(3-P-acetamido benzene sulfonyl base)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (15) the fluoro-4-[4-of (S)-N-3-[3-(2-P-acetamido benzene sulfonyl base)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (16) the fluoro-4-[4-[3-of (S)-N-3-[3-(the fluoro-6-chloro-phenyl-of 2-)-5-methyl-4-isoxazole formyl radical]-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (17) the fluoro-4-[4-of (S)-N-3-[3-(2-hydroxy benzoyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (18) the fluoro-4-[4-of (S)-N-3-[3-(L-phenylalanyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (19) the fluoro-4-[4-of (S)-N-3-[3-(phenyl amino carbonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (20) the fluoro-4-[4-of (S)-N-3-[3-(phenyl amino thiocarbonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl methylacetamide;
    (21) (S)-N-3-(the fluoro-4-methanesulfonamido of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
    (22) (S)-N-3-(the fluoro-4-phenylsulfonamido of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
    (23) (S)-N-3-(the fluoro-4-of 3-is to Methyl benzenesulfonyl aminophenyl)-2-oxo-5-oxazolidinyl methylacetamide;
    (24) (S)-N-3-(the fluoro-4-brosyl of 3-aminophenyl)-2-oxo-5-oxazolidinyl methylacetamide;
    (25) (S)-N-3-(the fluoro-4-of 3-is to anisole sulfonamido phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
    (26) (S)-N-3-(the fluoro-4-p-nitrophenyl of 3-sulfonamido phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
    (27) (S)-N-3-(bromobenzene sulfonamido phenyl between the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methylacetamide;
    (28) (S)-N-3-(the fluoro-4-sulfanilamido of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
    (29) (S)-N-3-(the fluoro-4-metanilamido-of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
    (30) (S)-N-3-(the fluoro-4-acetparaminosalol of 3-phenylsulfonamido phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
    (31) (S)-N-3-(the fluoro-4-m-acetamino of 3-phenylsulfonamido phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
    (32) (S)-N-3-(the adjacent acetoxyl group phenylsulfonamido of the fluoro-4-of 3-phenyl)-2-oxo-5-oxazolidinyl methylacetamide;
    (33) the fluoro-4-[3-of (S)-N-3-[3-(the fluoro-6-chloro-phenyl-of 2-)-5-methyl-4-cycliton base] phenyl]-2-oxo-5-oxazolidinyl methylacetamide.
  3. 3. as shown in the formula the (preparation method of I) Suo Shi oxazolidinone compounds or its pharmacy acceptable salt
    Figure A0215773500051
    In formula, R represents
    Figure A0215773500052
    or-NR 2r 3, wherein
    R 1=can substituted alkyl sulphonyl, can substituted aryl sulfonyl, can substituted aromatic heterocycle alkylsulfonyl, can substituted amino acid formyl radical, can substituted aryl formyl radical, can substituted aryl-amino-carbonyl, can substituted arylamino thioformyl;
    R 2=can substituted alkyl sulphonyl, can substituted aryl sulfonyl, can substituted aryl formyl radical, can substituted aromatic heterocycle formyl radical;
    R 3=H or alkyl,
    Described method is characterised in that and comprises the steps:
    (1) the fluoro-4-of (S)-N-[3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methyl] ethanamide and sulfonyl agent react 0.1-48 hour in-10～80 ℃ in non-polar solvent, obtains compound 1-9;
    (2) compound 6-8 carries out catalytic hydrogenation and obtains compound 10-12 in polar solvent under metal catalyst exists;
    (3) compound 10-12 carries out acetylization reaction 0.1-12 hour in-10～80 ℃ in non-polar solvent, obtains compound 13-15;
    (4) aryl formic acid acyl chlorides and the fluoro-4-of (S)-N-[3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methyl] O.1-48 ethanamide hour obtain compound 16,17,18 in-10～80 ℃ of reactions in non-polar solvent; Or aryl formic acid or amino acid and N-hydroxy-succinamide (HOSU) or-hydroxybenzotriazole (HOBt) or dicyclohexyl carbodiimide (DCC) react, and then and the fluoro-4-of (S)-N-[3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methyl] ethanamide obtains compound 16 for 0.1-48 hour in-10～80 ℃ of reactions in non-polar solvent, 17,18;
    (5) as required, be prepared into corresponding salt.
  4. 4. method as claimed in claim 3, the sulphonic acid anhydride that wherein sulfonyl agent described in (1) is selected from the SULPHURYL CHLORIDE that can be replaced by alkyl or aryl, the sulfuryl bromide that can be replaced by alkyl or aryl, can be replaced by alkyl or aryl; Non-polar solvent is selected from benzene, toluene, methylene dichloride, chloroform, tetrahydrofuran (THF).
  5. 5. method as claimed in claim 4, wherein said sulfonyl agent is alkyl or aryl SULPHURYL CHLORIDE, non-polar solvent is benzene, reacts on 0～20 ℃ and carries out 8-24 hour.
  6. 6. method as claimed in claim 3, wherein the polar solvent described in (2) is selected from methyl alcohol, ethanol and acetic acid, and metal catalyst is palladium/carbon or other catalyzer containing palladium or nickel.
  7. 7. method as claimed in claim 6, described polar solvent is methyl alcohol, and metal catalyst is palladium/carbon of 5% or 10%, and catalytic hydrogenation is carried out at normal temperatures and pressures.
  8. 8. as shown in the formula the (preparation method of I) Suo Shi oxazolidinone compounds or its pharmacy acceptable salt
    Figure A0215773500061
    In formula, R represents or-NR 2r 3, wherein
    R 1=can substituted alkyl sulphonyl, can substituted aryl sulfonyl, can substituted aromatic heterocycle alkylsulfonyl, can substituted amino acid formyl radical, can substituted aryl formyl radical, can substituted aryl-amino-carbonyl, can substituted arylamino thioformyl;
    R 2=can substituted alkyl sulphonyl, can substituted aryl sulfonyl, can substituted aryl formyl radical, can substituted aromatic heterocycle formyl radical;
    R 3=H or alkyl,
    Described method is characterised in that and comprises the steps:
    (1) (S)-N-[3-(the fluoro-4-aminophenyl of 3-)-2-oxo-5-oxazolidinyl methyl] ethanamide and sulfonyl agent react 0.1-48 hour in-10～80 ℃ in non-polar solvent, obtains compound 21-27;
    (2) compound 26-27 carries out catalytic hydrogenation 8-24 hour in 0 ℃ in polar solvent under metal catalyst exists in room temperature range, obtains compound 28-29;
    (3) compound 28-29 carries out acetylization reaction 0.1-12 hour in-10～80 ℃ in non-polar solvent, obtains compound 30-31;
    (4) aryl formic acid acyl chlorides and the fluoro-4-of (S)-N-[3-[3-(1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl methyl] ethanamide in-10～80 ℃ of reaction 0.1-48 hour, obtains compound 32-33 in non-polar solvent;
    (5) as required, be prepared into corresponding salt.
  9. 9. method as claimed in claim 8, the sulphonic acid anhydride that wherein sulfonyl agent described in (1) is selected from the SULPHURYL CHLORIDE that can be replaced by alkyl or aryl, the sulfuryl bromide that can be replaced by alkyl or aryl, can be replaced by alkyl or aryl; Non-polar solvent is pyridine, reacts on 0～20 ℃ and carries out 8-24 hour.
  10. 10. method as claimed in claim 8, wherein the polar solvent described in (2) is selected from methyl alcohol, ethanol and acetic acid, and metal catalyst is palladium/carbon or other catalyzer containing palladium or nickel.
  11. 11. methods as claimed in claim 10, wherein said polar solvent is methyl alcohol, and metal catalyst is palladium/carbon of 5% or 10%, and catalytic hydrogenation is carried out at normal temperatures and pressures.
  12. (I) Suo Shi oxazolidinone compounds or its salt application on the medicine of preparation treatment infectious diseases of 12. formulas.
  13. 13. application as claimed in claim 12, wherein infectious diseases is the microbial infection of multidrug resistance.
CN 02157735 2002-12-25 2002-12-25 Oxazolidone compound, preparing method and use thereof Expired - Fee Related CN1237056C (en)

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Cited By (9)

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Publication number Priority date Publication date Assignee Title
CN100395270C (en) * 2006-05-25 2008-06-18 湖北大学 Linear polystyrene supported (4S)-5,5-disubstituted oxazolidin one and its preparation method and uses
CN100406455C (en) * 2006-02-20 2008-07-30 中国科学院上海药物研究所 Oxazolidinone analog compound containing triazol radical and its preparation method and uses
CN100467455C (en) * 2007-02-14 2009-03-11 浙江工业大学 Synthetic method for 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isooxazole formyl chloride
CN100545150C (en) * 2003-09-12 2009-09-30 中国科学院上海药物研究所 Contain pyridine ring De oxazolidone compounds, Preparation method and use
US7825122B2 (en) 2005-12-14 2010-11-02 Amgen Inc. Diaza heterocyclic sulfonamide derivatives and their uses
WO2010058423A3 (en) * 2008-11-20 2010-12-09 Panacea Biotec Ltd. Novel antimicrobials
CN101914174A (en) * 2010-07-28 2010-12-15 湖北大学 Linear polystyrene-supported (4S)-oxazolidine-2-benzimine as well as preparation method and application thereof
CN101948552A (en) * 2010-08-27 2011-01-19 湖北大学 Linear polystyrene-supported chiral oxazolidine-2-selenium ketone and preparation method thereof
CN113603683A (en) * 2015-07-17 2021-11-05 结核病药物开发全球联盟公司 Substituted phenyl oxazolidinones for antimicrobial therapy

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100545150C (en) * 2003-09-12 2009-09-30 中国科学院上海药物研究所 Contain pyridine ring De oxazolidone compounds, Preparation method and use
US7825122B2 (en) 2005-12-14 2010-11-02 Amgen Inc. Diaza heterocyclic sulfonamide derivatives and their uses
CN100406455C (en) * 2006-02-20 2008-07-30 中国科学院上海药物研究所 Oxazolidinone analog compound containing triazol radical and its preparation method and uses
CN100395270C (en) * 2006-05-25 2008-06-18 湖北大学 Linear polystyrene supported (4S)-5,5-disubstituted oxazolidin one and its preparation method and uses
CN100467455C (en) * 2007-02-14 2009-03-11 浙江工业大学 Synthetic method for 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isooxazole formyl chloride
WO2010058423A3 (en) * 2008-11-20 2010-12-09 Panacea Biotec Ltd. Novel antimicrobials
US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
CN101914174A (en) * 2010-07-28 2010-12-15 湖北大学 Linear polystyrene-supported (4S)-oxazolidine-2-benzimine as well as preparation method and application thereof
CN101914174B (en) * 2010-07-28 2012-06-27 湖北大学 Linear polystyrene-supported (4S)-oxazolidine-2-benzimine as well as preparation method and application thereof
CN101948552A (en) * 2010-08-27 2011-01-19 湖北大学 Linear polystyrene-supported chiral oxazolidine-2-selenium ketone and preparation method thereof
CN113603683A (en) * 2015-07-17 2021-11-05 结核病药物开发全球联盟公司 Substituted phenyl oxazolidinones for antimicrobial therapy

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